U.S. patent number 8,927,015 [Application Number 12/297,147] was granted by the patent office on 2015-01-06 for formulations for delivering insulin.
This patent grant is currently assigned to Emisphere Technologies, Inc.. The grantee listed for this patent is William Elliott Bay, Nikhil Dhoot, Steven Dinh, Halina Levchik, Jun Liao, Puchun Liu, Shingai Majuru, Moses O. Oyewumi. Invention is credited to William Elliott Bay, Nikhil Dhoot, Steven Dinh, Halina Levchik, Jun Liao, Puchun Liu, Shingai Majuru, Moses O. Oyewumi.
United States Patent |
8,927,015 |
Levchik , et al. |
January 6, 2015 |
Formulations for delivering insulin
Abstract
Oral insulin formulations and processes for preparing oral
insulin formulations are provided.
Inventors: |
Levchik; Halina (Tarrytown,
NY), Oyewumi; Moses O. (Yorktown Heights, NY), Majuru;
Shingai (Brewster, NY), Bay; William Elliott
(Ridgefield, CT), Liao; Jun (Yorktown Heights, NY), Liu;
Puchun (Chappaqua, NY), Dinh; Steven (Briarcliff Manor,
NY), Dhoot; Nikhil (Dombivli, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Levchik; Halina
Oyewumi; Moses O.
Majuru; Shingai
Bay; William Elliott
Liao; Jun
Liu; Puchun
Dinh; Steven
Dhoot; Nikhil |
Tarrytown
Yorktown Heights
Brewster
Ridgefield
Yorktown Heights
Chappaqua
Briarcliff Manor
Dombivli |
NY
NY
NY
CT
NY
NY
NY
N/A |
US
US
US
US
US
US
US
IN |
|
|
Assignee: |
Emisphere Technologies, Inc.
(Roseland, NJ)
|
Family
ID: |
38610388 |
Appl.
No.: |
12/297,147 |
Filed: |
April 12, 2007 |
PCT
Filed: |
April 12, 2007 |
PCT No.: |
PCT/US2007/066560 |
371(c)(1),(2),(4) Date: |
October 14, 2008 |
PCT
Pub. No.: |
WO2007/121318 |
PCT
Pub. Date: |
October 25, 2007 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100151009 A1 |
Jun 17, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60791842 |
Apr 12, 2006 |
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60857747 |
Nov 7, 2006 |
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Current U.S.
Class: |
424/465; 514/5.9;
514/774 |
Current CPC
Class: |
A61K
9/06 (20130101); A61K 9/2013 (20130101); A61K
9/2027 (20130101); A61K 9/2063 (20130101); A61K
9/2077 (20130101); A61K 9/2095 (20130101); A61K
9/145 (20130101); A61K 9/2009 (20130101); A61K
38/28 (20130101) |
Current International
Class: |
A61K
38/28 (20060101); A61K 47/02 (20060101); A61K
47/42 (20060101); A61K 9/20 (20060101) |
Field of
Search: |
;424/465
;514/5.9,774 |
References Cited
[Referenced By]
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Primary Examiner: Schnizer; Richard
Assistant Examiner: Pipic; Alma
Attorney, Agent or Firm: Blank Rome LLP
Parent Case Text
CROSS REFERENCE TO PRIOR APPLICATIONS
This application is the U.S. national phase of International
Application No. PCT/US07/66560, filed Apr. 12, 2007, which claims
priority of Provisional Application No. 60/791,842 filed Apr. 12,
2006 and to Provisional Application No. 60/857,747 filed Nov. 7,
2006, the specifications of both of which are herein incorporated
by reference. The International Application was published in
English on Oct. 25, 2007 as WO 2007/121318 under PCT Article 21(2)
Claims
The invention claimed is:
1. A tablet consisting of 240 mg sodium
4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate, 12 mg gelatin, 5.45
mg insulin, 113.8 mg dibasic calcium phosphate and 3.75 mg
magnesium stearate.
Description
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations (e.g.
oral pharmaceutical formulations) containing insulin and one or
more delivery agents, e.g. (4-CNAB or sodium 4-CNAB), and methods
of treating subjects suffering from diabetes with such
pharmaceutical formulations.
BACKGROUND OF THE INVENTION
There is a need for orally administered insulin that provides
sufficient insulin bioavailability, and processes for preparing
such pharmaceutical compositions.
SUMMARY OF THE INVENTION
Methods of synthesizing pharmaceutical formulations containing
insulin and a delivery agent compound have an effect on the
bioavailability of the insulin upon administration of the
pharmaceutical formulation (e.g. upon oral administration by a
human). The present invention provides processing techniques that
facilitate the delivery of insulin upon administration with a
delivery agent compound.
One embodiment of the present invention is a solid oral
pharmaceutical composition comprising 4-CNAB, or a pharmaceutically
acceptable salt thereof, recombinant human insulin, povidone,
dibasic calcium phosphate, and magnesium stearate.
Another embodiment of the present invention is a process for
preparing a solid oral pharmaceutical formulation by introducing
insulin or an analog thereof to an aqueous solution that contains a
delivery agent compound, drying the solution to obtain an
insulin/delivery agent powder, optionally granulating the powder
with intragranular excipients, optionally adding extragranular
excipients to the powder or granules, and forming a unit dosage
form from the resulting composition (e.g., compressing the
composition into tablets or filling capsules with the
composition).
Another embodiment of the present invention is a process for
preparing a solid oral insulin pharmaceutical composition by (a)
preparing a solution of a delivery agent and insulin or an analog
thereof; (b) freeze-drying the insulin/delivery agent solution; (c)
milling the insulin/delivery agent colyophilized powder obtained by
freeze-drying the insulin/delivery agent solution; (d) mixing the
milled co-lyophilized powder with intragranular excipients; (e) dry
granulating the mixture formed in step (d), (f) adding
extragranular excipients; and (g) forming a unit dosage form from
the resulting composition (e.g., compressing the composition into
tablets or filling capsules with the composition). Dry granulation
may be performed, for example, by roller compaction or slugging and
then milling the resulting product.
Another embodiment of the present invention is a process for
preparing a solid oral insulin pharmaceutical composition by (a)
preparing a solution of a delivery agent and insulin or an analog
thereof; (b) performing rotary evaporation on the insulin/delivery
agent solution; and (c) forming a unit dosage form from the product
of step (b) (e.g., tableting the insulin/delivery agent powder or
adding the insulin/delivery agent powder to capsules). This process
may further include one or more of the steps of (d) milling the
insulin/delivery agent powder obtained by rotary evaporation; (e)
mixing the milled powder with intragranular excipients; (f)
granulating the milled powder and intragranular excipients (e.g. by
dry granulation), and (g) adding extragranular excipients. Dry
granulation may be performed, for example, by roller compaction or
slugging and milling.
Another embodiment of the present invention is a pharmaceutical
composition that includes (a) insulin or an insulin analog, (b) a
delivery agent and (c) a gelatin, as that term is used herein (e.g.
including gelatin alternatives).
Another embodiment of the present invention is a process for
preparing an oral insulin pharmaceutical composition by introducing
(a) a delivery agent compound and (b) insulin or an insulin analog
into gelatin or a gelatin alternative. In a preferred embodiment,
gelatin is optionally milled and mixed with a delivery agent. The
mixture is then granulated using an aqueous dispersion of insulin
or an insulin analog.
Another embodiment of the present invention is a method of
solubilizing insulin or an insulin analog by introducing a delivery
agent (e.g. 4-CNAB or sodium 4-CNAB) to an aqueous solution and
subsequently adding insulin or an insulin analog to the delivery
agent-containing solution. In one embodiment, the delivery agent is
added to water, sodium hydroxide is added to increase the pH of the
solution (e.g., to increase the pH to about 7 or 8), and then
insulin is added to the pH-adjusted solution.
Yet another embodiment is a method of treating diabetes in a
subject by administering a therapeutically effective amount of the
pharmaceutical composition of the present invention to the subject.
The diabetic subject can be a human suffering from Type I or Type
II diabetes. Generally, the insulin preparation of the present
invention does not induce any significant incidence of antibodies.
Preferably, the subject is administered the pharmaceutical
composition of the present invention for at least once day for at
least 90 days. According to a preferred embodiment, the
pharmaceutical composition is administered as adjunctive therapy to
a biguanide (such as metformin). According to another preferred
embodiment, the pharmaceutical composition is administered as
adjunctive therapy to a biguanide (such as metformin), acarbose, a
glitazone (e.g., pioglitazone), or a combination thereof.
One embodiment is a method of treating diabetes (e.g. type II
diabetes) in a subject who has not sufficiently responded to
metformin monotherapy, by administering a therapeutically effective
amount of the pharmaceutical composition of the present invention
to the subject. According to a preferred embodiment, the subject
continues treatment with metformin while also being treated with
the pharmaceutical composition of the present invention. According
to another preferred embodiment, the pharmaceutical composition is
administered as adjunctive therapy to a biguanide (such as
metformin), acarbose, a glitazone (e.g., pioglitazone), or a
combination thereof.
Yet another embodiment is a method of treating diabetes (e.g., Type
I or Type II diabetes) in a human having a hemoglobin A1c value of
at least about 8.0% by administering a therapeutically effective
amount of the pharmaceutical composition of the present invention
to the human. According to one embodiment, the human has a
hemoglobin Alc value ranging from about 8.0 to about 9.3%.
Preferably, the human is administered the pharmaceutical
composition of the present invention for at least once day for at
least 90 days.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 sets forth the solubility of recombinant human zinc insulin
at different pH and time-points.
FIG. 2 sets forth a solubility curve for insulin and 4-CNAB.
FIGS. 3 and 4 set forth insulin dissolution profiles in deionized
water.
FIGS. 5-12 set forth results of insulin dosage forms administered
to monkeys as described in Example 7.
FIGS. 13 and 14 set forth the results of insulin dosage forms
administered to humans as described in Example 23.
FIG. 15 sets forth the results of insulin dosage forms administered
to humans as described in Example 24.
FIG. 16 sets forth the results of insulin dosage forms administered
to humans as described in Example 25.
FIGS. 17-24 sets forth the results of insulin dosage forms
administered to humans as described in Example 26.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein and in the appended claims, the singular forms "a"
"an" and "the" also includes plural referents unless the context
clearly indicates otherwise. Thus, for example, reference to "a
molecule" includes one or more of such molecules, "a reagent"
includes one or more of such different reagents, reference to "an
antibody" includes one or more of such different antibodies, and
reference to "the method" includes reference to equivalent steps
and methods known to those of ordinary skill in the art that could
be modified or substituted for the methods described herein.
The term "hydrate" as used herein includes, but is not limited to,
(i) a substance containing water combined in molecular form and
(ii) a crystalline substance containing one or more molecules of
water of crystallization or a crystalline material containing free
water.
The term "solvate" as used herein includes, but is not limited to,
a molecular or ionic complex of molecules or ions of a solvent with
molecules or ions of the delivery agent compound or salt thereof,
or hydrate or solvate thereof.
The term "delivery agent" refers to any of the delivery agent
compounds disclosed or incorporated by reference herein.
The terms "alkyl", "alkoxy", "alkylene", "alkenylene",
"alkyl(arylene)", and "aryl(alkylene)" include, but are not limited
to, linear and branched alkyl, alkoxy, alkylene, alkenylene,
alkyl(arylene), and aryl(alkylene) groups, respectively.
Unless otherwise specified, the term "substituted" as used herein
includes, but is not limited to, substitution with any one or any
combination of the following substituents: halogens, hydroxide,
C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy.
The term "4-MOAC" refers to
8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid and
pharmaceutically acceptable salts thereof. Unless otherwise noted,
the term "4-MOAC" refers to all forms of 4-MOAC, including, but not
limited to, amorphous and crystalline forms of 4-MOAC.
The term "NAC" as used herein refers to
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid and pharmaceutically
acceptable salts thereof, including its monosodium salt. Unless
otherwise noted, the term "NAC" refers to all forms of NAC,
including, but not limited to, all amorphous and crystalline forms
of NAC. The term "SNAC" as used herein refers to the monosodium
salt of NAC, including, but not limited to, all amorphous and
crystalline forms of SNAC (such as those described in International
Publication No. WO 2005/107462, which is hereby incorporated by
reference), unless otherwise indicated.
The term "NAD" as used herein refers to
N-(10-[2-hydroxybenzoyl]-amino) decanoic acid and pharmaceutically
acceptable salts thereof, including, but not limited to, its
monosodium salt. Unless otherwise noted, the term "NAD" refers to
all forms of NAD, including, but not limited to, all amorphous and
crystalline forms of NAD. The term "SNAD" as used herein refers to
the monosodium salt of NAD, including, but not limited to, all
amorphous and crystalline forms of SNAC.
The term "5-CNAC" refers to
N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic acid (also known as
8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid)) and
pharmaceutically acceptable salts thereof, including, but not
limited to, its monosodium salt and disodium salt. Unless otherwise
noted, the term "5-CNAC" refers to all forms of 5-CNAC, including,
but not limited to, all amorphous and crystalline forms of it
(including those described in International Publication No. WO
00/59863, PCT/US2006/036455, filed Sep. 18, 2006, and U.S.
Provisional Application No. 60/718,829, filed Sep. 19, 2005, all of
which are hereby incorporated by reference).
The term "4-CNAB" refers to
4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (also known as
4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid) and
pharmaceutically acceptable salts thereof, including, but not
limited to, its monosodium salt. Unless otherwise noted, the term
"4-CNAB" refers to all forms of 4-CNAB, including, but not limited
to, all amorphous and crystalline forms of 4-CNAB. The term
"mono-sodium 4-CNAB" refers to monosodium
4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate, including, but not
limited to, anhydrous, monohydrate, and isopropanol solvates
thereof and amorphous and crystalline forms thereof (including
those described in International Publication Nos. WO 02/02509 and
WO 03/057650, both of which is hereby incorporated by reference),
unless otherwise indicated.
The term "HPOD" refers to 8-(2-hydroxyphenoxy)octyldiethanolamine
and pharmaceutically acceptable salts thereof, including, but not
limited to, its meslyate salt. Unless otherwise noted, the term
"HPOD" refers to all forms of HPOD, including, but not limited to,
all amorphous and crystalline forms of HPOD and includes anhydrous,
monohydrate, and isopropanol solvates of HPOD, including those
described in International Publication No. WO 2005/115406, which is
hereby incorporated by reference).
The term "insulin analog" as used herein, refers to analogs of
naturally occurring insulins, including human insulin or animal
insulins, which differ by substitution of at least one naturally
occurring amino acid residue with other amino acid residues and/or
addition/removal of at least one amino acid residue from the
corresponding, otherwise identical, naturally occurring insulin.
Insulin analogs have a physiological effect similar to that of
naturally occuring or recombinant human insulin. The added and/or
replaced amino acid residues can also be those which do not occur
naturally. Insulin analogs include those analogs disclosed in U.S.
Pat. Nos. 6,960,561, 6,906,028, 6,852,694, 6,777,207, 6,630,348,
6,551,992, 6,534,288, 6,531,448, RE37,971, 6,465,426, 6,444,641,
6,335,316, 6,268,335, 6,051,551, 6,034,054, 5,970,973, 5,952,297,
5,922,675, 5,888,477, 5,873,358, 5,747,642, 5,693,609, 5,650,486,
5,646,242, 5,547,929, 5,504,188, 5,474,978, 5,461,031, 5,135,866,
4,421,685, all of which are hereby incorporated by reference.
The term "subject" as used herein includes a mammal, preferably a
human. It may also mean other animals, including other mammals, but
especially birds, poultry or other avian forms.
The phrase "pharmaceutically acceptable" refers to components or
compositions that are physiologically tolerable.
The term "treating" or "treatment" of a state, disorder or
condition includes:
(1) preventing or delaying the appearance of clinical symptoms of
the state, disorder or condition developing in a subject that may
be afflicted with or predisposed to the state, disorder or
condition but does not yet experience or display clinical or
subclinical symptoms of the state, disorder or condition;
(2) inhibiting the state, disorder or condition, i.e., arresting or
reducing the development of the disease or at least one clinical or
subclinical symptom thereof; or
(3) relieving the disease, i.e., causing regression of the state,
disorder or condition or at least one of its clinical or
subclinical symptoms.
The benefit to a subject to be treated is either statistically
significant or at least perceptible to the subject or to the
physician.
The term "mean", when preceding a pharmacokinetic value (e.g., mean
peak) represents the arithmetic mean value of the pharmacokinetic
value unless otherwise specified.
The term "Serum Concentration" or "Serum Concentration Curve" is
the graphic representation of the amount of drug in an animal's
(including humans) plasma at particular points in time.
The term "Area Under the Curve" or "Area Under the Concentration
Curve" or "AUC" means the area present beneath the line of the
graphical representation of plasma concentrations versus time in
subject(s). Unless otherwise specified, AUC refers to the AUC
obtained based on baseline adjusted concentrations, i.e.,
concentrations obtained after subtracting the individual baseline
from each individual time point (C.sub.t-C.sub.0).
The term "Cmax" refers to the maximum observed concentration taken
directly from the plasma concentration-time course profile. Unless
otherwise specified, Cmax refers to Cmax obtained based on baseline
adjusted concentrations, i.e., concentrations obtained after
subtracting the individual baseline from each individual time point
(C.sub.t-C.sub.0).
Delivery Agent Compounds
In one embodiment of the present invention, the delivery agent
compound has the following structure, or a pharmaceutically
acceptable salt thereof:
##STR00001##
wherein Ar is phenyl or naphthyl; Ar is optionally substituted with
one or more of --OH, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4
haloalkoxy; R.sup.7 is C.sub.4-C.sub.20 alkyl, C.sub.4-C.sub.20
alkenyl, phenyl, naphthyl, (C.sub.1-C.sub.10 alkyl)phenyl,
(C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10 alkyl)naphthyl,
(C.sub.1-C.sub.10 alkenyl)naphthyl, phenyl(C.sub.1-C.sub.10 alkyl),
phenyl(C.sub.1-C.sub.10 alkenyl), naphthyl(C.sub.1-C.sub.10 alkyl),
or naphthyl(C.sub.1-C.sub.10 alkenyl); R.sup.8 is hydrogen, C.sub.1
to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; R.sup.7 is optionally
substituted with C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4
alkenyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy,
--OH, --SH, --CO.sub.2R.sub.9, or any combination thereof; R.sup.9
is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2 to C.sub.4
alkenyl; and R.sup.7 is optionally interrupted by oxygen, nitrogen,
sulfur or any combination thereof.
In one embodiment, the delivery agent compounds are not substituted
with an amino group in the position alpha to the acid group.
Suitable delivery agent compounds include, but are not limited to,
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid and salts thereof,
e.g., a sodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid,
such as a mono- or di-sodium salt,
N-(8-[2-hydroxybenzoyl]-amino)decanoic acid and pharmaceutically
acceptable salts thereof, including its monosodium salt,
4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (also known as
4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate) and pharmaceutically
acceptable salts thereof, including its sodium salt (e.g.,
monosodium salt), N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic
acid (also known as 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic
acid)) and pharmaceutically acceptable salts thereof, including its
monosodium salt, and 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic
acid and pharmaceutically acceptable salts thereof, including its
monosodium salt.
According to one embodiment, R.sup.7 in Formula A is selected from
C.sub.8-C.sub.20 alkyl, C.sub.8-C.sub.20 alkenyl, phenyl, naphthyl,
(C.sub.1-C.sub.10 alkyl)phenyl, (C.sub.1-C.sub.10 alkenyl)phenyl,
(C.sub.1-C.sub.10 alkyl) naphthyl, (C.sub.1-C.sub.10
alkenyl)naphthyl, phenyl(C.sub.1-C.sub.10 alkyl),
phenyl(C.sub.1-C.sub.10 alkenyl), naphthyl(C.sub.1-C.sub.10 alkyl),
and naphthyl(C.sub.1-C.sub.10 alkenyl).
According to another embodiment, R.sup.7 in Formula A is selected
from C.sub.8-C.sub.20 alkyl, and C.sub.8-C.sub.20 alkenyl.
In another embodiment of the present invention, the delivery agent
compound has the following structure, or a pharmaceutically
acceptable salt thereof:
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--OH, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8, --NO.sub.2,
--NR.sup.9R.sup.10, or --N.sup.+R.sup.9R.sup.10R.sup.11(R.sup.12);
R.sup.5 is H, --OH, --NO.sub.2, halogen, --CF.sub.3,
--NR.sup.14R.sup.15, --N.sup.+R.sup.14, R.sup.15,
R.sup.16(R.sub.13), amide, C.sub.1-C.sub.12 alkoxy,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, carbamate,
carbonate, urea, or --C(O)R.sup.18; R.sup.5 is optionally
substituted with halogen, --OH, --SH, or --COOH; R.sup.5 is
optionally interrupted by O, N, S, or --C(O)--; R.sup.6 is a
C.sub.1-C.sub.12 alkylene, C.sub.2-C.sub.12 alkenylene, or arylene;
R.sup.6 is optionally substituted with a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sub.8; R.sup.6 is optionally
interrupted by O or N; R.sup.7 is a bond or arylene; R.sup.7 is
optionally substituted with --OH, halogen, --C(O)CH.sub.3,
--NR.sup.10R.sup.11, or
--N.sup.-R.sup.10R.sup.11R.sup.12(R.sup.13).sup.-; each occurrence
of R.sup.8 is independently H, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, or --NH.sub.2; R.sup.9, R.sup.10,
R.sup.11, and R.sup.12 independently H or C.sub.1-C.sub.10 alkyl;
R.sup.13 is a halide, hydroxide, sulfate, tetrafluoroborate, or
phosphate; R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, or --C(O)R.sup.17; R.sup.17 is --OH,
C.sub.1-C.sub.10 alkyl, or C.sub.2-C.sub.12 alkenyl; and R.sup.18
is H, C.sub.1-C.sub.6 alkyl, --OH, --NR.sub.14R.sub.15, or
N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13)--.
In one particular embodiment, when R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are H, and R.sup.7 is a bond then R.sup.6 is
not a C.sub.1-C.sub.6, C.sub.9 or C.sub.10 alkyl.
In another embodiment, when R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are H, R.sup.5 is --OH, and R.sup.7 is a bond then R.sup.6 is not a
C.sub.1-C.sub.3 alkyl.
In yet another embodiment, when at least one of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 is not H, R.sup.5 is --OH, and R.sup.7 is a
bond, then R.sup.6 is not a C.sub.1-C.sub.4 alkyl.
In yet another embodiment, when R.sup.1, R.sup.2, and R.sup.3 are
H, R.sup.4 is --OCH.sub.3, R.sup.5 is --C(O)CH.sub.3, and R.sup.6
is a bond then R.sup.7 is not a C.sub.3 alkyl.
In yet another embodiment, when R.sup.1, R.sup.2, R.sup.4, and
R.sup.5 are H, R.sup.3 is --OH, and R.sup.7 is a bond then R.sup.6
is not a methyl.
In yet another embodiment, R.sup.6 of Formula B is a
C.sub.8-C.sub.12 alkylene, C.sub.8-C.sub.12 alkenylene, or
arylene.
In yet another embodiment of the present invention, the delivery
agent compound has the following structure or a pharmaceutically
acceptable salt thereof:
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
independently H, --CN, --OH, --OCH.sub.3, or halogen, at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN; and
R.sup.6 is a C.sub.1-C.sub.12 linear or branched alkylene, a
C.sub.1-C.sub.12 linear or branched alkenylene, a C.sub.1-C.sub.12
linear or branched arylene, an alkyl(arylene) or an
aryl(alkylene).
According to one embodiment, when R.sup.1 is --CN, R.sup.4 is H or
--CN, and R.sup.2, R.sup.3, and R.sup.5 are H, then R.sup.6 is not
methylene ((CH.sub.2).sub.1).
In another embodiment, R.sup.6 of Formula C is a C.sub.8-C.sub.12
linear or branched alkylene, a C.sub.8-C.sub.12 linear or branched
alkenylene, an arylene, an alkyl(arylene) or an aryl(alkylene).
In yet another embodiment, R.sup.6 of Formula C is a
C.sub.8-C.sub.12 linear or branched alkylene, a C.sub.8-C.sub.12
linear or branched alkenylene.
Other suitable delivery agent compounds are disclosed in U.S. Pat.
No. 6,627,228, which is hereby incorporated by reference.
The delivery agent compound can also be a a polymeric delivery
agent comprising a polymer conjugated to a modified amino acid or
derivative thereof via a linkage group selected from the group
consisting of --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--,
--COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2NH--, --NHCH.sub.2--,
--CH.sub.2NHC(O)O--, --OC(O)NHCH.sub.2--,
--CH.sub.2NHCOCH.sub.2O--, --OCH.sub.2C(O)NHCH.sub.2--,
--NHC(O)CH.sub.2O--, --OCH.sub.2C(O)NH--, --NH--, --O--, and
carbon-carbon bond. In one embodiment, the polymeric delivery agent
is not a polypeptide or polyamino acid. In another embodiment, the
modified amino acid has the structure of formula A, B, or C. In one
embodiment, the polymeric delivery agent includes a modified amino
acid having the structure:
##STR00004## which is conjugated via a --COO group to a polymer
having monomers derived from polyethylene glycol.
In one embodiment, the polymeric delivery agent is a modified amino
acid having the structure of Formula D conjugated via a --COO group
to a polymer having the structure:
--CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.xCH.sub.2CH.sub.2O--Y,
wherein x is from 1-14; and Y is H or CH.sub.3.
According to another embodiment, the polymeric delivery agent is
compound having the structure of Formula D conjugated via a --COO
group to a polymer having the structure:
--CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.xCH.sub.2CH.sub.2O--Y,
wherein x is 1-5; and Y is CH.sub.3 or H.
For example, the polymeric delivery agent can be
8-(2-hydroxybenzoylamino)-octanoic acid
2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-ethoxy)ethoxy]ethoxy}eth-
yl ester.
Other suitable delivery agent compounds include compounds of the
formula below and pharmaceutically acceptable salts thereof:
##STR00005## R.sub.1 is --(CH.sub.2).sub.m--R.sub.8, wherein m is 0
or 1; R.sub.2-R.sub.6 are independently selected from hydrogen,
hydroxyl, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 alkoxy, and cyano; R.sub.7
is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
and C.sub.2-C.sub.10 alkynyl; R.sub.8 is selected from cyclopentyl,
cyclohexyl and phenyl, wherein when R.sub.8 is phenyl, m is 1; and
R.sub.8 is optionally substituted with C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen or hydroxyl, or a combination
thereof.
Other delivery agent compounds of the present invention include
those of the formula:
##STR00006## and pharmaceutically acceptable salts thereof,
wherein: R.sub.1 is a C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkenyl, R.sub.2-R.sub.6 are independently selected from hydrogen,
hydroxyl, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 alkoxy, and cyano, and
R.sub.7 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10
alkenyl, and C.sub.2-C.sub.10 alkynyl.
Other suitable delivery agent compounds include those of the
formula:
##STR00007## and pharmaceutically acceptable salts thereof, wherein
n is 1 to 9, and R.sup.1 to R.sup.5 are independently hydrogen,
C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.2 to
C.sub.6 alkenyl, halogen, hydroxyl, --NH--C(O)--CH.sub.3, or
--O--C.sub.6H.sub.5.
In one embodiment, R.sup.1 to R.sup.5 of Formula G are
independently hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.1 to
C.sub.4 alkoxy, C.sub.2 to C.sub.4 alkenyl, halogen, or
hydroxyl.
Other suitable delivery agent compounds include those of the
formula:
##STR00008## and pharmaceutically acceptable salts thereof, wherein
R.sup.1 to R.sup.4 are independently hydrogen, C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, halogen, C.sub.1 to C.sub.4
alkoxy, or hydroxyl.
Other delivery agent compounds of the present invention include
those of the formula:
##STR00009## and pharmaceutically acceptable salts thereof, wherein
one of R.sup.1 to R.sup.5 is --(CH.sub.2).sub.n--COOH where n is
0-6; and the remaining four members of R.sup.1 to R.sup.5 are
independently hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.2 to
C.sub.4 alkenyl, halogen, C.sub.1 to C.sub.4 alkoxy, or hydroxyl;
and R.sub.6-R.sub.10 are independently hydrogen, C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, halogen, C.sub.1 to C.sub.4
alkoxy, or hydroxyl.
Other delivery agents of the present invention include compounds
represented by the formula:
##STR00010## and pharmaceutically acceptable salts thereof, wherein
n is 1 to 9; and R.sub.1 to R.sub.9 are independently hydrogen,
C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, halogen,
C.sub.1 to C.sub.4 alkoxy, or hydroxyl.
Other suitable delivery agent compounds include those of the
formula:
##STR00011## and pharmaceutically acceptable salts thereof, wherein
R.sup.1-R.sup.5 are independently hydrogen, C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, halogen, C.sub.1 to C.sub.4
alkoxy, hydroxyl, or --O--(CH.sub.2).sub.n--COOH (where n is 1 to
12); at least one of R.sup.1 to R.sup.5 is --O--(CH2).sub.nCOOH
where n is 1-12; and R.sup.6-R.sup.10 are independently hydrogen,
C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, halogen,
C.sub.1 to C.sub.4 alkoxy, or hydroxyl.
Suitable delivery agents are described in International.
Publication Nos. WO 2005/117854 and WO 2005/112633, both of which
were filed May 16, 2005 and their priority documents, U.S.
Provisional Application Nos. 60/576,088, filed Jun. 1, 2004, U.S.
Provisional Application No. 60/576,397, filed Jun. 1, 2004, U.S.
Provisional Application No. 60/576,105, filed Jun. 1, 2004, U.S.
Provisional Application No. 60/571,090, filed May 14, 2004, U.S.
Provisional Application No. 60/571,092, filed May 14, 2004, U.S.
Provisional Application No. 60/571,195, filed May 14, 2004, U.S.
Provisional Application No. 60/571,194, filed May 14, 2004, U.S.
Provisional Application No. 60/571,093, filed May 14, 2004, U.S.
Provisional Application No. 60/571,055, filed May 14, 2004, U.S.
Provisional Application No. 60/571,151, filed May 14, 2004, U.S.
Provisional Application No. 60/571,315, filed May 14, 2004, U.S.
Provisional Application No. 60/571,144, filed May 14, 2004, and
U.S. Provisional Application 60/571,089, filed May 14, 2004, all of
which are hereby incorporated by reference in their entirety.
Other suitable delivery agents include those having the following
structure and pharmaceutically acceptable salts thereof:
##STR00012##
wherein (a) R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently H, --OH, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8,
--NO.sub.2, --NR.sup.9R.sup.10, or
--N.sup.+R.sup.9R.sub.10R.sup.11(Y.sup.-); R.sup.8 is hydrogen,
--OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkyl substituted with
halogen or --OH, C.sub.2-C.sub.4 alkenyl unsubstituted or
substituted with halogen or --OH, or --NR.sup.14R.sup.15; R.sup.9,
R.sup.10, and R.sup.11 are independently hydrogen, oxygen,
C.sub.1-C.sub.4 alkyl unsubtituted or substituted with halogen or
--OH, C.sub.2-C.sub.4 alkenyl unsubstituted or substituted with
halogen or --OH; Y is halide, hydroxide, sulfate, nitrate,
phosphate, alkoxy, perchlorate, tetrafluoroborate, carboxylate,
mesylate, fumerate, malonate, succinate, tartrate, acetate,
gluconate, maleate; R.sup.5 is H, --OH, --NO.sub.2, halogen,
CF.sub.3, --NR.sup.14R.sup.15,
--N.sup.+R.sup.14R.sup.15R.sup.16(Y.sup.-), amide, C.sub.1-C.sub.12
alkoxy, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl,
carbamate, carbonate, urea, or --C(O)R.sup.22; R.sup.5 is
optionally substituted with halogen, --OH, --SH, or --COOH; R.sup.5
is optionally interrupted by O, N, S, or --C(O)--; R.sup.14,
R.sup.15, and R.sup.16 are independently H or C.sub.1-C.sub.10
alkyl; R.sup.22 is H, C.sub.1-C.sub.6 alkyl, --OH,
--NR.sup.14R.sup.15; R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.16 alkylene, C.sub.2-C.sub.16 alkenylene,
C.sub.2-C.sub.16 alkynylene, C.sub.5-C.sub.16 arylene,
(C.sub.1-C.sub.16 alkyl) arylene or aryl(C.sub.1-C.sub.16
alkylene); R.sup.6 is optionally substituted with C.sub.1-C.sub.7
alkyl or C.sub.1-C.sub.7 cycloalkyl; R.sup.7 is --NR.sup.18R.sup.19
or N.sup.+R.sup.18R.sup.19R.sup.20Y.sup.-; R.sup.18 and R.sup.19
are independently hydrogen, oxygen, hydroxy, substituted or
unsubstituted C.sub.1-C.sub.16 alkyl, substituted or unsubstituted
C.sub.2-C.sub.16 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.16 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted alkylcarbonyl (e.g. substituted or
unsubstituted (C.sub.1-6 alkyl)carbonyl), substituted or
unsubstituted arylcarbonyl, substituted or unsubstituted
alkanesulfinyl (e.g. substituted or unsubstituted (C.sub.1-6
alkane)sulfinyl), substituted or unsubstituted arylsulfinyl,
substituted or unsubstituted alkanesulfonyl (e.g. substituted or
unsubstituted (C.sub.1-6 alkane)sulfonyl), substituted or
unsubstituted arylsulfonyl, substituted or unsubstituted
alkoxycarbonyl (e.g. substituted or unsubstituted (C.sub.1-6
alkoxy)carbonyl), or substituted or unsubstituted aryloxyccarbonyl,
or substituted or unsubstituted C.sub.5-C.sub.7 heterocyclic ring
(i.e., 5, 6, or 7-membered heterocyclic ring), wherein the
substitutions may be halogen or --OH; and R.sup.20 is independently
hydrogen, substituted or unsubstituted C.sub.1-C.sub.16 alkyl,
substituted or unsubstituted C.sub.2-C.sub.16 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.16 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkylcarbonyl
(e.g. substituted or unsubstituted (C.sub.1-6 alkyl)carbonyl),
substituted or unsubstituted arylcarbonyl, substituted or
unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted
(C.sub.1-6 alkane)sulfinyl), substituted or unsubstituted
arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g.
substituted or unsubstituted (C.sub.1-6 alkane)sulfonyl),
substituted or unsubstituted arylsulfonyl, substituted or
unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted
(C.sub.1-6 alkoxy)carbonyl), or substituted or unsubstituted
aryloxycarbonyl; or (b) R.sup.1-R.sup.16 and R.sup.20 are as
defined above; and R.sup.18 and R.sup.19 combine to form a 5, 6, or
7-membered heterocyclic ring optionally interrupted with an oxo
group and unsubstituted or substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, aryl, aryloxy, or carbocyclic ring.
According to one embodiment, R.sup.7 is morpholino, morpholinium
salt, or diethanolamino.
According to another embodiment, R.sup.6 is a C.sub.1-C.sub.16
alkylene and R.sup.7 is morpholino or a morpholinium salt.
Preferably, R.sup.6 is C.sub.4-C.sub.12 alkylene, such as an
unsubstituted C.sub.4-C.sub.12 alkylene. More preferably, R.sup.6
is C.sub.4-C.sub.10, C.sub.4-C.sub.8, or C.sub.6-C.sub.8 alkylene,
such as an unsubstituted C.sub.4-C.sub.10, C.sub.4-C.sub.8, or
C.sub.6-C.sub.8 alkylene. According to one embodiment, one of
R.sup.1-R.sup.5 is hydroxy, for example, R.sup.1 can be
hydroxy.
According to yet another embodiment, when R.sup.6 is a
C.sub.1-C.sub.10 alkylene, at most one of R.sup.2 and R.sup.4 is
halogen. According to another embodiment, R.sup.6 is a
C.sub.8-C.sub.16, C.sub.9-C.sub.16, C.sub.10-C.sub.16, or
C.sub.11-C.sub.16 alkylene. For instance, R.sup.6 may be a C.sub.8,
C.sub.9, C.sub.10, C.sub.11, or C.sub.12 alkylene (e.g., a normal
C.sub.8-C.sub.12 alkylene). According to yet another embodiment, at
most one of R.sup.1 and R.sup.5 is alkyl.
According to yet another embodiment, R.sup.1 is hydroxy and
R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently hydrogen
or halogen.
According to yet another embodiment, R.sup.2 is hydroxy and
R.sup.1, R.sup.3, R.sup.4, and R.sup.5 are independently hydrogen
or halogen.
According to yet another embodiment, R.sup.3 is hydroxy and
R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are independently hydrogen
or halogen.
In a preferred embodiment, halogen is F, Cl or Br, more preferably
F or Cl, and even more preferably Cl.
According to yet another embodiment, R.sup.6 is C.sub.1-C.sub.16
alkylene, (C.sub.1-C.sub.16 alkyl) arylene or aryl(C.sub.1-C.sub.16
alkylene). More preferably R.sup.6 is C.sub.1-C.sub.12 alkylene,
more preferably C.sub.3-C.sub.10 alkylene, more preferably
C.sub.4-C.sub.10 or C.sub.4-C.sub.8 alkylene, and more preferably
C.sub.6-C.sub.8 alkylene. More preferably, R.sup.6 is
unsubstituted.
According to yet another embodiment, R.sup.7 is --NR.sup.18R.sup.19
and R.sup.18 and R.sup.19 are independently C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, or butyl) substituted with --OH. In
another embodiment, R.sup.7 is --NR.sup.18R.sup.19 and R.sup.18 and
R.sup.19 combine to form a six membered heterocyclic ring
substituted with an oxo group.
According to one preferred embodiment, R.sup.1 is hydrogen;
R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, halogen,
--OH, or --OCH.sub.3; R.sup.5 is hydrogen, --OH, or --C(O)CH.sub.3;
R.sup.6 is C.sub.1-C.sub.12 alkylene, and R.sup.7 wherein R.sup.18
and R.sup.19 combine to form a 5, 6 or 7 membered heterocyclic
ring.
According to another preferred embodiment, one of R.sup.3, R.sup.4,
and R.sup.5 is hydroxy and the others are independently halogen or
hydrogen; R.sup.1 and R.sup.2 are independently halogen or
hydrogen; R.sup.6 is C.sub.1-C.sub.16 alkylene; and R.sup.7 is
NR.sup.18R.sup.19 wherein R.sup.18 and R.sup.19 combine to form a
5, 6, or 7 membered heterocyclic ring. R.sup.6 is preferably
C.sub.6-C.sub.16, C.sub.6-C.sub.10, C.sub.8-C.sub.16,
C.sub.10-C.sub.16, or C.sub.4-C.sub.8 alkylene, such as
unsubstituted C.sub.6-C.sub.16, C.sub.6-C.sub.10, C.sub.8-C.sub.16,
C.sub.10-C.sub.16, or C.sub.4-C.sub.8 alkylene. Preferably,
R.sup.18 and R.sup.19 form a morpholino or imidazole.
In another preferred embodiment, R.sup.1 is hydrogen; R.sup.2,
R.sup.3, and R.sup.4 are independently hydrogen, halogen, --OH, or
--OCH.sub.3; R.sup.5 is hydrogen, --OH, or --C(O)CH.sub.3; R.sup.6
is C.sub.1-C.sub.12 alkylene; and R.sup.7 is
N.sup.+R.sup.18R.sup.19R.sup.20(Y.sup.-) wherein R.sup.18 and
R.sup.19 are hydroxy substituted C.sub.1-C.sub.16 alkyl and
R.sup.20 is hydrogen.
In another preferred embodiment, R.sup.1 is hydrogen; R.sup.2,
R.sup.3, and R.sup.4 are independently hydrogen, halogen, --OH, or
--OCH.sub.3; R.sup.5 is hydrogen, --OH, or --C(O)CH.sub.3; R.sup.6
is C.sub.1-C.sub.12 alkylene; and R.sup.7 is
N.sup.+R.sup.18R.sup.19R.sup.20(Y.sup.-) wherein R.sup.18 and
R.sup.19 are hydroxy substituted C.sub.1-C.sub.16 alkyl and
R.sup.20 is hydrogen.
In another preferred embodiment, R.sup.1, R.sup.2, R.sup.4, R.sup.5
are independently halogen or hydrogen; R.sup.3 is --OH, or
--OCH.sub.3; and R.sup.7 is
N.sup.+R.sup.18R.sup.19R.sup.20(Y.sup.-) wherein R.sup.18 and
R.sup.19 are hydroxy substituted C.sub.1-C.sub.16 alkyl and
R.sup.20 is hydrogen.
According to one preferred embodiment, R.sup.1 is hydrogen;
R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, halogen,
--OH, or --OCH.sub.3; R.sup.5 is hydrogen, --OH, or --C(O)CH.sub.3;
R.sup.6 is C.sub.1-C.sub.6 alkylene or aryl substituted
C.sub.1-C.sub.12 alkyl; and R.sup.7 is --NR.sup.18R.sup.19 wherein
R.sup.18 and R.sup.19 combine to form a 5, 6, or 7 membered
heterocyclic ring or N.sup.+R.sup.18R.sup.19R.sup.20(Y.sup.-)
wherein R.sup.18 and R.sup.19 are hydroxy substituted
C.sub.1-C.sub.16 alkyl and R.sup.20 is hydrogen.
In another preferred embodiment, the citrate salt of the delivery
agent is used.
Other suitable delivery agents include those having the following
structure and pharmaceutically acceptable salts thereof:
##STR00013##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--OH, halogen, --OCH.sub.3, --NR.sup.10R.sup.11 or
--N.sup.+R.sup.10R.sup.11R.sup.12 (R.sup.13).sup.-; R.sup.5 is H,
--OH, --NO.sub.2, --NR.sup.14R.sup.15,
--N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13).sup.-, amide,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, carbamate,
carbonate, urea, or --C(O)R.sup.18; R.sup.5 is optionally
substituted with --OH, --SH, or --COOH; R.sup.5 is optionally
interrupted by O, N, S, or --C(O)--; R.sup.6 is a C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 alkenylene, or arylene; R.sup.6 is
optionally substituted with a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sup.9; R.sup.6 is optionally
interrupted by O or N; R.sup.7 is a bond or arylene; R.sup.7 is
optionally substituted with --OH, halogen, --C(O)CH.sub.3,
--NR.sup.10R.sup.11 or
--N.sup.+R.sup.10R.sup.11R.sup.12(R.sup.13).sup.-; R.sup.8 is H or
C.sub.1-C.sub.4 alkyl; R.sup.9 is H, C.sub.1-C.sub.4 alkyl, or
C.sub.2-C.sub.4 alkenyl; R.sup.10, R.sup.11, and R.sup.12 are
independently H or C.sub.1-C.sub.10 alkyl; R.sup.13 is a halide,
hydroxide, sulfate, tetrafluoroborate, or phosphate; R.sup.15, and
R.sup.16 are independently H, C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.12 alkenyl, O, or --C(O)R.sup.17; R.sup.17 is --OH,
C.sub.1-C.sub.10 alkyl, or C.sub.2-C.sub.12 alkenyl; and R.sup.18
is --OH, C.sub.1-C.sub.6 alkyl, --NR.sup.14R.sup.15,
--N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13).sub.-.
According to one embodiment, when R.sup.5 is OCH.sub.3 then R.sup.6
is C.sub.1-C.sub.8 or C.sub.10-C.sub.12 alkyl.
According to a preferred embodiment, R.sup.5 is not --OCH.sub.3.
More preferably, R.sup.5 is not alkoxy.
According to another preferred embodiment, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are hydrogen, R.sup.5 is --COOH,
--C(O)NH.sub.2, --C(O)CH.sub.3, or --NO.sub.2, R.sup.6 is
--(CH.sub.2).sub.7--, and R.sup.7 is a bond.
According to yet another preferred embodiment, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are hydrogen, R.sup.5 is --C(O)NH.sub.2,
R.sup.6 is --CH.sub.2--, and R.sup.7 is a para-phenylene.
According to one embodiment, the delivery agents of formula (6)
have the formula:
##STR00014##
wherein R.sup.19 is --NO.sub.2 or --C(O)R.sup.23; R.sup.20 is a
C.sub.1-C.sub.12 alkylene or C.sub.1-C.sub.12 alkenylene; R.sup.21
is a bond or arylene; R.sup.22 is H or C.sub.1-C.sub.4 alkyl; and
R.sup.23 is --OH, C.sub.1-C.sub.6 alkyl, or --NH.sub.2.
The delivery agent compound can also be any of those described in
U.S. Pat. Nos. 6,699,467, 6,663,898, 6,693,208, 6,693,073,
6,693,898, 6,663,887, 6,646,162, 6,642,411, 6,627,228, 6,623,731,
6,610,329, 6,558,706, 6,525,020, 6,461,643, 6,461,545, 6,440,929,
6,428,780, 6,413,550, 6,399,798, 6,395,774, 6,391,303, 6,384,278,
6,375,983, 6,358,504, 6,346,242, 6,344,213, 6,331,318, 6,313,088,
6,245,359, 6,242,495, 6,221,367, 6,180,140, 6,100,298, 6,100,285,
6,099,856, 6,090,958, 6,084,112, 6,071,510, 6,060,513, 6,051,561,
6,051,258, 6,001,347, 5,990,166, 5,989,539, 5,976,569, 5,972,387,
5,965,121, 5,962,710, 5,958,451, 5,955,503, 5,939,381, 5,935,601,
5,879,681, 5,876,710, 5,866,536, 5,863,944, 5,840,340, 5,824,345,
5,820,881, 5,811,127, 5,804,688, 5,792,451, 5,776,888, 5,773,647,
5,766,633, 5,750,147, 5,714,167, 5,709,861, 5,693,338, 5,667,806,
5,650,386, 5,643,957, 5,629,020, 5,601,846, 5,578,323, 5,541,155,
5,540,939, 5,451,410, 5,447,728, 5,443,841, and 5,401,516;
International Publication Nos. WO94/23767, WO95/11690, WO95/28920,
WO95/28838, WO96/10396, WO96/09813, WO96/12473, WO97/36480, WO
2004/4104018, WO 2004080401, WO 2004062587, WO 2003/057650, WO
2003/057170, WO 2003/045331, WO 2003/045306, WO 2003/026582, WO
2002/100338, WO 2002/070438, WO 2002/069937, WO 02/20466, WO
02/19969, WO 02/16309, WO 02/15959, WO 02/02509, WO 01/92206, WO
01/70219, WO 01/51454, WO 01/44199, WO 01/34114, WO 01/32596, WO
01/32130, WO 00/07979, WO 00/06534, WO 00/06184, WO 00/59863, WO
00/59480, WO 00/50386, WO 00/48589, WO 00/47188, WO 00/46182, WO
00/40203, WO 99/16427, WO 98/50341, WO 98/49135, WO 98/34632, WO
98/25589, WO 98/21951, WO 97/47288, WO 97/31938, WO 97/10197, WO
96/40076, WO 96/40070, WO 96/39835, WO 96/33699, WO 96/30036, WO
96/21464, WO 96/12475, and WO 96/12474; and U.S. Published
Application Nos. 20040110839, 20040106825, 20040068013,
20040062773, 20040022856, 20030235612, 20030232085, 20030225300,
20030198658, 20030133953, 20030078302, 20030072740, 20030045579,
20030012817, 20030008900, 20020155993, 20020127202, 20020120009,
20020119910, 20020102286, 20020065255, 20020052422, 20020040061,
20020028250, 20020013497, 20020001591, 20010039258, and
20010003001. Each of the above listed U.S. patents and U.S. and
International published applications are herein incorporated by
reference.
Non-limiting examples of delivery agent compounds include
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid,
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid,
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,
8-(2,6-dihydroxybenzoylamino)octanoic acid,
8-(2-hydroxy-5-bromobenzoylamino)octanoic acid,
8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-iodobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methylbenzoylamino)octanoic acid,
8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid,
8-(3-hydroxyphenoxy)octanoic acid, 8-(4-hydroxyphenoxy)octanoic
acid, 6-(2-cyanophenoxy)hexanoic acid,
8-(2-Hydroxyphenoxy)octyl-diethanolamine,
8-(4-hydroxyphenoxy)octanoate, 8-(4-hydroxyphenoxy)octanoate,
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)-octanoic acid, and salts
thereof. Preferred salts include, but are not limited to,
pharmaceutically acceptable salts thereof such as the monosodium
and disodium salts.
The delivery agent compounds may be in the form of the carboxylic
acid or pharmaceutically acceptable salts thereof, such as sodium
salts, and hydrates and solvates thereof. The salts may be mono- or
multi-valent salts, such as monosodium salts and disodium salts.
The delivery agent compounds may contain different counter ions
chosen for example due to their effect on modifying the dissolution
profile of the carrier.
The delivery agent compounds may be prepared by methods known in
the art, such as those discussed in the aforementioned publications
(e.g., International Publication Nos. WO 98/34632, WO 00/07979, WO
01/44199, WO 01/32596, WO 02/20466, and WO 03/045306). SNAC, SNAD,
and the free acid and other salts thereof may be prepared by
methods known in the art, such as those described in U.S. Pat. Nos.
5,650,386 and 5,866,536.
Salts of the delivery agent compounds of the present invention may
be prepared by methods known in the art. For example, sodium salts
may be prepared by dissolving the delivery agent compound in
ethanol and adding aqueous sodium hydroxide.
The delivery agent compound may be purified by recrystallization or
by fractionation on one or more solid chromatographic supports,
alone or linked in tandem. Suitable recrystallization solvent
systems include, but are not limited to, acetonitrile, methanol,
and tetrahydrofuran. Fractionation may be performed on a suitable
chromatographic support such as alumina, using methanol/n-propanol
mixtures as the mobile phase; reverse phase chromatography using
trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and
ion exchange chromatography using water or an appropriate buffer as
the mobile phase. When anion exchange chromatography is performed,
preferably a 0-500 mM sodium chloride gradient is employed.
Solutions Containing a Delivery Agent Compound and Insulin or an
Analog thereof
Some processes of the present invention involve the introduction of
a delivery agent and insulin into an aqueous solution and obtaining
a powder from this solution (e.g. by lyophillization or rotary
evaporation). Generally water is used as the solvent, although the
solvent can also comprise or consist essentially of other solvents
which dissolve the delivery agent (e.g. sodium 4-CNAB) and insulin.
For example, ethanol, methanol, isopropyl alcohol, tetrahydrofuran,
dioxane, butanol, acetone, 2-butanone, methyl tert-butyl ether,
n-propanol, methylene chloride, and other similar low boiling point
solvents could be used in lieu of, or in combination with,
water.
Once obtained, the powder (which contains insulin and a delivery
agent compound) may be further processed (e.g. milled or granulated
with other excipeints) and compressed into tablets or filled into
capsules.
Gelatin Based Pharmaceutical Formulations
Gelatin is a mixture of purified protein fractions that may be
obtained by partial hydrolysis of animal collagen by an acid or an
alkaline. The process of acid hydrolysis is referred to as Type A
and that by alkaline hydrolysis is referred to as Type B. Gelatin
is a linear polymer that is comprised of amino acids which could
result in a molecular weight ranging from 15,000 to 250,000. As
used herein, the term gelatin includes acid and alkaline
hydrolysates of animal collagen.
Gelatin may be applied in formulations of the present invention to
serve many functions, such as a coating, a suspending agent, tablet
binder and/or as a viscosity-increasing agent. Insulin/delivery
agent tablets (e.g. insulin/sodium 4-CNAB) may be formulated at
various concentrations of gelatin and at various ratios of insulin
and delivery agent.
In water, gelatin swells and softens and it can absorb between 5-10
times its own weight of water. There are several hydrophilic
natural and synthetic polymers may be applied, in certain
embodiments, in place of gelatin. For example, (a) anionic
polymers: alginic acid, dextran sulfate, pectin; (b) cationic acid:
chitosan, polylysine; (c) amphiphatic polymers: carboxylmethyl
chitin, fibrin; (d) neutral polymers such as dextran, agarose,
pullulan.
As used herein, the term gelatin includes gelatin and gelatin
alternatives disclosed in Remington's Pharmaceutical Sciences,
16.sup.th ed., Mack Publishing Company, Easton, Pa. (1980), page
1245 and pages 1576-1582, which is hereby incorporated by reference
in its entirety. The term gelatin also includes compositons
disclosed in U.S. Pat. No. 6,090,915, U.S. Pat. No. 4,043,996, U.S.
Pat. No. 4,064,008, U.S. Pat. No. 4,176,117, U.S. Pat. No.
4,889,920, U.S. Pat. No. 4,374,063, U.S. Pat. No. 5,210,182, U.S.
Pat. No. 4,232,425, U.S. Pat. No. 4,402,873, U.S. Pat. No.
4,427,583, U.S. Pat. No. 5,093,474, U.S. Pat. No. 5,288,408 and
U.S. Pat. No. 5,459,241, each of which is hereby incorporated by
reference in their entirety.
The term gelatin, as used herein also includes gelatin substitutes
and alternatives. Generally, such a gelatin alternative can be made
from easily obtainable (e.g. vegetable) materials having a
homogeneous composition and having all the essential
characteristics of gelatin. In the manufacture of soft gel films
and capsules, the soft gel composition preferably possesses the
properties of good wet and dry film strength, insolubility in cold
water, oil, and alcohol, solubility in hot water, temperature and
pressure sealability, film clarity, film flexibility, edibility,
inertness to drugs or other materials to be encapsulated, and rapid
setting from a hot liquid to form a gel.
One gelatin alternative is a film-forming composition that
comprises starch material selected from modified starch and waxy
starch; gum; and plasticizer as disclosed in U.S. Pat. No.
6,375,981, which is hereby incorporated by reference. The modified
starch or waxy starch preferably has a dextrose equivalent (DE) of
less than about 1, and more preferably has no measurable DE. This
composition can be, but is not required to be, 100% gelatin-free.
Thus, the composition can be used as a gelatin replacement, or as
an extender in gelatin formulations.
Another gelatin alternative is wheat fiber gel as disclosed in U.S.
Pat. No. 6,440,480, which is hereby incorporated by reference.
Wheat fiber gel is made by thermal/physical processing of wheat
fiber. A special milling technique is used for treating wheat
material resulting in a product containing a large proportion of
microfine particles. Specific improvements are obtained by mixing
the product with maltodextrin. The product so obtained is sold
under the tradename Vitacel.RTM., by FMC Biopolymer of
Philadelphia, Pa. This product is a dry powder, which readily
disperses in water. Upon stirring of the dispersion the gel forms
through shear forces. It is reported that wheat fiber gel can be
used as a gelatin replacer in yogurt or ice cream. (I. I.
Bollinger, Food Marketing & Techn. October 1995, 4-6).
Carrageenan is yet another gelatin alternative. Carrageenan is a
natural hydrocolloid, a polysaccharide hydrocolloid, which is
derived from seaweed. It comprises a carbohydrate polymer of
repeating sugar units, which is linear, without significant numbers
of branches or substitutions.
Methods of Treatment
The present invention also provides methods for treating a subject
with impaired glucose tolerance or with early or late stage
diabetes comprise orally administering to the mammal a
pharmaceutical formulation of the present invention that includes a
therapeutically effective amount of insulin or an insulin analog
and a delivery agent in an amount effective to facilitate the
absorption of the insulin.
The pharmaceutical formulations may also include a biguanide such
as metformin, as disclosed in International Application No.
PCT/US05/27499, which is hereby incorporated by reference.
It is preferred that the administration be on a chronic basis,
e.g., for at least two weeks. In various embodiments, the
administration is preprandially and at bedtime such that, after two
weeks of treatment, the subject achieves improved glucose tolerance
and glycemic control, as well as improved insulin utilization,
insulin sensitivity, insulin secretion capacity and/or HbA.sub.1c
levels, as compared with baseline levels prior to treatment.
Improved glucose tolerance and better endogenous capacity of the
subject to handle sugar load can also be measured by an AUC of
blood glucose excursion, following a glucose load, that is reduced
by a statistically significant amount as compared with AUC of blood
glucose excursion, following a glucose load, prior to
treatment.
Improved glycemic control can be demonstrated by: decreased fasting
blood glucose levels as measured by fasting blood glucose
concentration that is reduced by a statistically significant amount
as compared with baseline fasting blood glucose concentration prior
to treatment. decreased serum fructosamine concentrations, as
measured by serum fructosamine assay, that is reduced by a
statistically significant amount as compared with baseline serum
fructosamine concentrations prior to treatment. improved HbA1c
levels after treatment compared with baseline levels prior to
treatment. Preferably, the improved HbA1c levels are measured by a
statistically significant decline in HbA1c levels. When treating a
mammal with impaired glucose tolerance or with early or late stage
diabetes, administration of the pharmaceutical formulation of the
present invention can preferably be made to a mammal having an
HbA.sub.1c level ranging from normal to elevated prior to
treatment.
Improved insulin utilization and insulin sensitivity of the
subject's body can be measured by a statistically significant
decline in HOMA (Homeostasis Model Assessment). Improved insulin
secretion capacity of the subject's body may also be measured by
Stumvoll first-phase insulin secretion capacity index.
In preferred embodiments of the invention, by virtue of the chronic
administration of oral dosage forms of the present invention, the
subject achieves improved glucose tolerance and glycemic control as
compared with baseline levels prior to treatment even without any
statistically significant increase in weight, any statistically
significant increase in risk of hypoglycemia or any statistically
significant increase in risk of hyperinsulinemia in the mammal over
the treatment period, and without the need for monitoring the
mammal's blood glucose concentrations or HbA.sub.1c levels.
Further, by virtue of the chronic administration of oral dosage
forms of the present invention, the subject achieves improved
insulin utilization, insulin sensitivity insulin secretion capacity
and HbA.sub.1c levels as compared with baseline levels prior to
treatment.
It is preferred that the administration of the oral pharmaceutical
formulation is administered 1-4 or more times daily, preprandially
and/or at bedtime. In one embodiment of the invention,
administration of the pharmaceutical formulation takes place once
daily, either at bedtime or preprandially for one meal during the
day time, e.g., for breakfast, lunch or dinner. In another
embodiment, administration of the pharmaceutical formulation takes
place multiple times daily, preferably at bedtime and preprandially
for one meal during the day time, e.g., for breakfast, lunch or
dinner. In a further embodiment, administration of the
pharmaceutical formulation takes place multiple times daily,
preferably at bedtime and preprandially for more than one meal
during the day time. Administration of the pharmaceutical
formulation can also be at or shortly prior to bedtime and
concurrently with or shortly prior to ingestion of each meal, i.e.,
within about 15 minutes or less of ingestion of each meal.
Preferably, the insulin formulations are administered to human
patients on a chronic basis, e.g., for at least about two weeks.
The dosage form of the present invention can be administered for at
least one day, for one week, for two weeks, for longer periods, for
alternating on-off time periods, or for the life of the
patient.
The frequency of administration of the oral pharmaceutical
formulation, on a daily basis (i.e., how often during one day-night
period) and on a chronic basis (i.e., for how many days), may
depend upon the patient's position along a "diabetes continuum",
i.e., the extent of the patient's impaired glucose tolerance, the
patient's stage of diabetes and the patient's need for exogenous
glycemic control. This continuum ranges from normal glycemic
control, to simple impaired glucose tolerance and insulin
resistance seen in pre-diabetics or early stage type 2 diabetics,
to failure of insulin production by the pancreas seen in type 1
diabetics and late stage type 2 diabetics. This can also be
measured by the patient's HbA.sub.1c concentration, ranging from
normal to elevated levels (e.g., a HbA1C value of 8.0% or
greater).
For example, if the subject has a need for fasting glycemic
control, the oral pharmaceutical formulation should preferably be
administered only at or shortly prior to bedtime. If the subject
has some need for post-prandial glycemic control, the oral
pharmaceutical formulation should preferably be administered
preprandially for some meals. If the subject has a need for total
post-prandial glycemic control, the oral pharmaceutical formulation
should preferably be administered preprandially for all meals. If
the subject has a need for comprehensive glycemic control, the oral
pharmaceutical formulation should preferably be administered
preprandially for all meals and at or shortly prior to bedtime.
Embodiments of the present invention also provide a method of
achieving glucose homeostasis in subjects, comprising orally
administering to a subject a pharmaceutical formulation comprising
a therapeutically effective amount of insulin or an insulin analog
and a delivery agent in an amount effective to facilitate the
absorption of the insulin or insulin analog. It is preferred that
the administration be on a chronic basis, e.g., for at least two
weeks, and be preprandially and at bedtime such that, after two
weeks of treatment, the mammal achieves improved glucose tolerance
and glycemic control as compared with baseline levels prior to
treatment.
Examples
The following examples illustrate the invention without limitation.
All parts are given by weight unless otherwise indicated.
Example 1
Solubilization of Insulin
The solubility of recombinant human zinc insulin obtained from
Diosynth France (distributed in the U.S. through Diosynth, Inc.)
(hereafter insulin type #1) and Eli Lilly Co. (hereafter insulin
type #2) was determined in aqueous solutions having various pH
values at 37.degree. C. Excess insulin was added to buffer
solutions at pH values of 1, 2, 3, 4, 5, 6, 6.8, and 7.4. Vials
containing the solutions were shaken in a constant temperature
water bath, and visually observed at regular time intervals.
Samples were taken at 2 hours, 4 hours, and 24 hours and analyzed
by a stability-indicating HPLC method. The results are shown below
in Table 1:
TABLE-US-00001 TABLE 1 pH-solubility data of Diosynth and Lilly
insulin at 37.degree. C. Insulin concentration Insulin
concentration Insulin concentration (mg/ml), 2 h (mg/ml), 4 h
(mg/ml), 24 h insulin insulin insulin insulin insulin insulin pH
type # 1 type # 2 type # 1 type # 2 type # 1 type # 2 1.23 >2,
deg* >2, deg >4, deg >4, deg 0.814, deg deg 2.02 >2,
deg >2, deg --, deg --, deg >4, deg >2, deg 3.02 0.989,
deg 0.797, deg 1.092, deg 0.814, deg 0.826, deg 0.731, deg 4.05
0.066 0.068 0.0317 0.040 0.147, deg 0.128, deg 5.07 0.156 0.091
0.155 0.094 0.165, deg 0.124, deg 6.08 0.066 0.049 0.0612 0.044
0.126, deg 0.229, deg 6.82 1.852 0.947 >2 1.294 >4 >2 7.42
>2 >2 >4 >4 >4 >4 deg - products of degradation
present in chromatograms
Visual observation indicated that insulin type #1 dissolved faster
than insulin type #2. This difference was not observed at pH 1, 2,
and 7.4 where dissolution was very rapid for both insulin types.
Solubility at pH 1, 2 and 7.4 was in excess of 4 mg/mL. Solubility
at pH 6.8 was greater than 4 mg/mL for insulin type #1 and 2 mg/mL
for insulin type #2, but complete dissolution occurred only after
overnight shaking. The difference in the dissolution rate of
insulin type #2 was most apparent at this pH. Both types of insulin
exhibited some degradation at pH 3, 4, 5, and 6 after 24 hours of
shaking. As expected, solubility was lowest around pH 5, with the
solubilities at pH 4, 5, and 6 all being around 0.1 mg/mL.
The results for pH 3-6.8 are shown in FIG. 1.
Example 2
Solubilization of Insulin in Solutions Containing a Delivery
Agent
The solubility of insulin was investigated in aqueous solutions
containing varying amounts of the delivery agent compound sodium
4-CNAB. The aqueous solution containing delivery agent was adjusted
to pH 1 by the addition of 1N HCl and excess insulin was added to
the acidified solution. Thereafter, the pH of the solution was
increased by the addition of increments of 1N NaOH. Vials
containing the suspensions were left without shaking or sonicating
for 1-2 hours. The supernatant was analyzed for insulin and sodium
4-CNAB using an HPLC method and the pH was recorded. This process
was repeated with increased amounts of delivery agent added to the
solution until the insulin was completely solubilized. All of these
experiments were performed at room temperature. The results are set
forth below in Table 2.
TABLE-US-00002 TABLE 2 pH of Delivery Delivery Agent, Insulin,
Delivery Agent Agent solution (mg/mL) (mg/mL) None (DI water) 6.3
-- 1.14 4-CNAB 6.4 5 0.5 6.45 10 1 6.26 50 11 6.49 50 44 6.71 100
86 6.45 100 >110 6.83 150 187 6.79 200 >135 SNAC 7.9 150
>200 HPOD 3.9 250 >50
The results for 4-CNAB and Insulin are also shown in FIG. 2.
Example 4
Solubilization of Insulin Tablet
A 300 mg pellet of insulin was prepared in a die. The surface area
of the pellet available to the dissolution medium was 0.484
cm.sup.2. The pellet was compressed at 1200-1400 lbs on a Carver
press to form discs. The die was then attached to the shaft of a
dissolution apparatus (USP Dissolution Type II (Paddle) made by
Vankel). The die was rotated at 100 rpm and then immersed in 500 mL
of degassed dissolution medium maintained at 37.degree. C.
Dissolution experiments were conducted in water and in aqueous
solutions containing sodium 4-CNAB. Samples of the solutions were
taken over two hours and analyzed by HPLC. FIGS. 3 and 4 show
dissolution profiles of insulin in deionized (DI) water and in 10
mg/mL sodium 4-CNAB solution, respectively.
The rate of insulin dissolution was significantly greater in the 10
mg/mL sodium 4-CNAB dissolution media than the deionized water
dissolution media.
The experiments were repeated in 50 mg/ml sodium 4-CNAB dissolution
media. The insulin levels in these solutions were below the
detection limits of the HPLC technique used.
Example 6
Lyophilized Insulin/4-CNAB Formulations
Lyophilization as a method of co-drying insulin/4-CNAB solutions to
obtain co-dried insulin/sodium 4-CNAB powder was investigated. The
3 formulations shown in Table 5 were prepared as follows.
Initially, 4-CNAB was used to solubilize the insulin. The required
amounts of insulin and sodium 4-CNAB were weighed out. The sodium
4-CNAB was added to the required amount of water (about 20 ml of
water per gram of sodium 4-CNAB) and stirred (1-5 minutes) until
completely dissolved. The corresponding amount of insulin was then
dispersed in the sodium 4-CNAB solution and left without stirring,
shaking or sonicating for 0.5-2 hours until solution became clear.
The solution was lyophilized using the cycle in shown in Table
4.
TABLE-US-00003 TABLE 4 The freeze-drying cycle for Insulin/4-CNAB
solutions. Temperature .degree. C. Time (minutes) Pressure (Torr)
-10 30 -45 30 500 -35 1200 100 -35 240 50 25 1440 25
TABLE-US-00004 TABLE 5 Formulation Formulation Formulation
Components 1 2 3 Recombinant Human Insulin 1.8 mg 1.8 mg 1.8 mg (50
Units) (Strenght: 27.5 Units/mg) 4-CNAB Monosodium Salt 80 mg 160
mg 240 mg Dibasic Calcium Phosphate 36 mg 46 mg 79.75 mg Magnesium
stearate 1.2 mg 2.2 mg 3.55 mg Total Weight/tablet 119 mg 210 mg
325 mg
Tablets were prepared by mixing the lyophilized insulin/4CNAB
powder, dibasic calcium phosphate and magnesium stearate. The
powder mixture was compressed into tablets using a single punch
Korsch EK-0 tablet press to prepare an initial compact. Granules
were obtained by crushing the initial compact in a mortar and
passing the granules through a 35 mesh sieve. The granules were
compressed into tablets of a predetermined weight and stored in a
freezer at -20.degree. C.
Example 7
In-Vivo Primate Studies
The formulations of Example 6 were fed to rhesus monkeys. The
monkeys were fasted for at least 12 hrs prior to dosing and up to 4
hrs after dosing. Water was withheld approximately 1 hr before
dosing and up to 2 hrs after dosing after which it was permitted ad
libitum. The dosing was followed by a 5 ml water flush. Blood
samples (approximately 2 ml each) were collected by venipuncture at
15 minutes before dosing (t=0) and at 5, 10, 15, 20, 30, 45 minutes
and 1, 1.5, 2, 3, 4 hr after dosing.
Four male primates were administered one tablet of Formulation 1 of
Example 6. The results are shown in FIG. 5 (glucose reduction) and
FIG. 6 (serum insulin concentrations). The averaged results are
shown in FIG. 7. After a wash-out period, the same group of four
primates were each administered Formulation 2 of Example 6. These
results are shown in FIGS. 8-10.
A different group of four male primates were each administered one
tablet of Formulation 3 of Example 6. Glucose reduction is shown in
FIG. 11. Serum insulin levels for 3 of the four monkeys are shown
in FIG. 12.
Example 8
Preparation of Tablets Containing Co-Lyophilized Insulin/4-CNAB
Powder
Tablets containing co-lypophilized insulin/sodium 4-CNAB powder and
having the formulation shown in Table 6 were prepared as follows.
First, insulin was dissolved in an aqueous solution containing
sodium 4-CNAB and the solution was freeze dried according to the
regimen in Table 4. The insulin/4-CNAB solution obtained from
freeze-drying was then milled with a 35 mesh sieve and blended with
copovidone and magnesium stearate (intragranular excipents). The
composition was then dry granulated by roller compaction.
Copovidone and magnesium stearate was added extragranularly and the
granules were compressed into tablets at a pressure of about 1000
psi for 5 seconds.
Based on the process, tablets with the following amounts of
ingredients were prepared:
TABLE-US-00005 TABLE 6 Insulin/4-CNAB (150 units/240 mg)
Co-lyophilized Tablets Ingredients Weight (mg/tablet) Weight/Batch
(g) Insulin/4-CNAB (Co-lyophilized 5.45/240 270.0 containing 150
Units of insulin) Copovidone; NF/EP 3.60 3.96 (intragranular)
Magnesium Stearate; 0.90 0.99 NF/EP(intragranular) Copovidone;
NF/EP 3.60 3.96 (extragranular) Dibasic Calcium Phosphate 103.75
114.13 Anhydrous, USP/EP Magnesium Stearate 2.70 2.97 Theoretical
Tablet Weight 360 mg
Example 9
Preparation of Tablets Containing Co-Lyophilized Insulin/4-CNAB
Powder
Tablets containing co-lyophilized insulin/4-CNAB and having the
formulation shown in Table 7 were prepared by the procedure set
forth in Example 8.
TABLE-US-00006 TABLE 7 Insulin/4-CNAB (150 units/400 mg)
Co-lyophilized Tablets Ingredients Weight (mg/tablet) Weight/Batch
(g) *Insulin/4-CNAB 5.45/400 430.588 (Co-lyophilized) (Containing
150 units of Insulin) Copovidone; NF/EP 5.80 6.160 (intragranular)
Magnesium Stearate; NF/EP 1.40 1.487 (intragranular) Copovidone;
NF/EP 5.75 6.106 (extragranular) Dibasic Calcium Phosphate 157.20
166.946 Anhydrous, USP/EP Magnesium Stearate 4.40 4.673 Theoretical
Tablet Weight 580 mg
Example 10
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
Sodium 4-CNAB (935.7 g, 0.4 wt % water by Karl Fisher titration)
and purified water (4850 mL) were charged to a 20 L, borosilicate,
rotary evaporator flask. The flask was attached to a rotary
evaporator and rotated at about 60 rpm until the solids dissolved.
The rotation was stopped. The flask was removed from the rotary
evaporator and insulin (64.1 g, 27.4 U/mg) was added. The flask was
re-attached to the rotary evaporator and the insulin was allowed to
dissolve without agitation. The water was removed rapidly with the
rotary evaporator bath set at about 45 C and the internal pressure
set at about 5 mm Hg. The walls of the rotary evaporator flask
became coated with solid co-dried insulin/4CNAB as the water was
removed. These solids were scraped from the walls of the flask and
dried in a vacuum oven set at full vacuum and 50.degree. C. until
the water content was less than 10 wt % by Karl Fisher analysis. In
most cases the vacuum drying time could be reduced by breaking up
the larger lumps of co-dried material about midway through the
vacuum oven drying cycle. The dried material was then hammer milled
so that it would pass through a 35 mesh screen. The milled, powdery
material was placed in a suitable container and stored in a freezer
at -20.degree. C. or lower until used. The recovery of co-dried
material was about 95%.
The co-dried insulin/4-CNAB prepared as described above, was mixed
with povidone and magnesium stearate in the amounts shown in Table
8 below and compressed into tablets tablets at a pressure of about
1000 psi for 5 seconds.
TABLE-US-00007 TABLE 8 Ingredient Amount 4-CNAB Sodium Salt 80 mg
Recombinant Human 150 Units (27.4 U/mg) Insulin Povidone, USP 1 mg
(Kollidon 90F) Magnesium stearate, NF 1 mg
Example 11
Preparation of Capsules Containing Co-dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder. 80 mg of sodium 4-CNAB/150 Units of insulin
was placed, without excipients, into size 2 hard gelatin opaque
white capsules.
Example 12
Preparation of Tablets Containing Co-dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 966.7 g of 4-CNAB, 5000 mL of
water and 33.23 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 9 were prepared by
the procedure set forth in Example 10:
TABLE-US-00008 TABLE 9 Ingredient Amount 4-CNAB Sodium Salt 80 mg
Recombinant Human 75 Units (27.4 U/mg) Insulin Povidone, USP 1 mg
(Kollidon 90F) Magnesium stearate, NF 1 mg
Example 13
Preparation of Capsules Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 966.7 g of 4-CNAB, 5000 mL of
water and 33.23 g of insulin were charged to the rotary evaporator
flask.
80 mg of sodium 4-CNAB/75 Units of insulin was placed, without
excipients, into size 2 hard gelatin opaque white capsules.
Example 14
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of Example 10 was repeated to prepare tablets, except
that povidone and magnesium stearate were not included in the
formulation.
Example 15
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of Example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 241.7 g of 4-CNAB, 1260 mL of
water and 8.3 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 10 were prepared by
the procedure set forth in Example 10.
TABLE-US-00009 TABLE 10 Ingredient Amount 4-CNAB Sodium Salt 160 mg
Recombinant Human 150 Units (27.4 U/mg) Insulin Povidone, USP 0 mg
(Kollidon 90F) Magnesium stearate, NF 0 mg
Example 16
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 245.8 g of 4-CNAB, 1280 mL of
water and 4.3 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 11 were prepared by
the procedure set forth in Example 10.
TABLE-US-00010 TABLE 11 Ingredient Amount 4-CNAB Sodium Salt 320 mg
Recombinant Human 150 Units (27.4 U/mg) Insulin Povidone, USP 0 mg
(Kollidon 90F) Magnesium stearate, NF 0 mg
Example 17
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 245.4 g of 4-CNAB, 1280 mL of
water and 5.6 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 12 were prepared by
the procedure set forth in Example 10.
TABLE-US-00011 TABLE 12 Ingredient Amount 4-CNAB Sodium Salt 160 mg
Recombinant Human 100 Units (27.4 U/mg) Insulin Povidone, USP 0 mg
(Kollidon 90F) Magnesium stearate, NF 0 mg
Example 18
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 247.2 g of 4-CNAB, 1300 mL of
water and 2.8 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 13 were prepared by
the procedure set forth in Example 10.
TABLE-US-00012 TABLE 13 Ingredient Amount 4-CNAB Sodium Salt 320 mg
Recombinant Human 100 Units (27.4 U/mg) Insulin Povidone, USP 0 mg
(Kollidon 90F) Magnesium stearate, NF 0 mg
Example 19
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 247.2 g of 4-CNAB, 1300 mL of
water and 2.8 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 14 were prepared by
the procedure set forth in Example 10.
TABLE-US-00013 TABLE 14 Ingredient Amount 4-CNAB Sodium Salt 320 mg
Recombinant Human 100 Units (27.4 U/mg) Insulin Povidone, USP 1 mg
(Kollidon 90F) Magnesium stearate, NF 1 mg
Example 20
Preparation of Tablets Containing Co-Dried Insulin/4-CNAB Powder
Obtained from Rotary Evaporation
The process of example 10 was repeated to prepare the co-dried
insulin/4-CNAB powder, except that 245.8 g of 4-CNAB, 1280 mL of
water and 4.3 g of insulin were charged to the rotary evaporator
flask.
Tablets having the formulation shown in Table 15 were prepared by
the procedure set forth in Example 10.
TABLE-US-00014 TABLE 15 Ingredient Amount 4-CNAB Sodium Salt 320 mg
Recombinant Human 150 Units (27.4 U/mg) Insulin Povidone, USP 1 mg
(Kollidon 90F) Magnesium stearate, NF 1 mg
Example 21
Preparation of Tablets Based on Granulated Gelatin-Based
Formulation
Tablets having the formulation shown in Table 16 were prepared as
follows. Gelatin was milled using a Kitchen-Aid.TM. coffee grinder
and later screened through a sieve of size #35. Afterwards, the
required amount of insulin was weighed and dispersed into purified
water. The amount of purified water used was about 15% of the
theoretical batch weight. For a theoretical batch size of 1200
tablets, 50 g of Insulin is dispersed in 46.7 g of purified
water.
Sodium 4-CNAB and the milled gelatin were transferred into an
appropriate sized high shear granulator and mixed for about 2
minutes. The sodium 4-CNAB and gelatin mixture was granulated first
with the aqueous dispersion of insulin and later with purified
water using a pump device. The resultant wet granules were evenly
dispersed in oven trays and dried in a vacuum oven
(Temperature=50.degree. C.; Vacuum=5 mm Hg) for at least 8 hours.
The dried granules were characterized based on moisture (0.5%) and
insulin content and insulin content uniformity. The granules were
milled and screened through a sieve of size 0.02 inches. Prior to
tablet compression, dibasic calcium phosphate and magnesium
stearate were blended with dry granules. Tablets were compressed
using an EKO single punch station press.
Based on the above procedure, tablets containing the following
amounts of ingredients were prepared.
TABLE-US-00015 TABLE 16 Weight Ingredients (mg/dose) Recombinant
Human Insulin 5.45 4-CNAB Monosodium salt 240 Gelatin (Type A) 12
Dibasic Calcium Phosphate (extragranular) 113.80 Magnesium Stearate
(extragranular) 3.75 Total Weight (mg/tablet) 375
The tablets prepared by this process had an average weight of about
373.5 mg, a thickness of 5 mm and an average hardness of about 10.3
kP.
Example 22
Preparation of Granulated Tablets (Wet Granulation)
Tablets having the formulation shown in Tables 17 and 18 were
prepared as follows.
TABLE-US-00016 TABLE 17 Drug Product Components: Insulin/4-CNAB
(150 Units/80 mg) Tablets Component Function 4-CNAB Sodium Salt
Delivery Agent Recombinant Human Insulin Drug (Active Agent)
Povidone, USP (Kollidon 90F) Binder Dibasic Calcium Phosphate,
Anhydrous, Binder USP Magnesium stearate, NF Lubricant Purified
Water, USP Granulating fluid
Sodium 4-CNAB was milled using a Quadro Comil equipped with a 35
mesh screen. Insulin and the milled sodium 4-CNAB were blended
together, and transferred to a Key Instruments KG 5 high shear
granulator equipped with a 5 Liter bowl. The material was
granulated with povidone. Once the addition of the povidone was
completed, the container was rinsed with small portions of purified
water and added to the granulation until the desired granulation
was achieved.
The granulation was transferred to clean stainless steel trays and
dried in a vacuum oven at 50.degree. C. until the moisture content
was less than 5.0% w/w and then milled through a 35 mesh screen and
further dried until the moisture content less than 1.5% w/w. The
granulation was assayed for insulin and sodium 4-CNAB using a
validated HPLC method. The insulin assay of the granulation was
used for calculating the required quantity of Emcompress for the
batch. The required amount of Emcompress was added to the
granulation and blending was performed in a V-blender for 15
minutes. Samples were collected for bend uniformity testing. After
acceptable blend uniformity data was obtained the required amount
of magnesium stearate was added and blending was performed for 3
minutes. The resulting blend was compressed into tablets using a
Korsch EKO single station tablet press. The target tablet weight
was 125 mg with a range of 119-131 mg, acceptable tablet hardness
range was 5-11 kP with a target tablet hardness of 7.0 kP. The
tablets exhibited an average thickness of 7.8 mm. The
Insulin/4-CNAB (150 Units/80 mg) tablets were packaged in a
container closure system consisting of a 60 cc HDPE Round, White
bottle with 33 mm Child Resistant Cap 1 with Safe-Gard.RTM. 75 m
Induction Innerseal and Cotton Coil 12 gm/yd.
Based on this procedure, the following amounts of ingredients were
used to prepare the tablets:
TABLE-US-00017 TABLE 18 Drug Product Composition: Insulin/4-CNAB
(150 Units/80 mg) Tablets (Batch Size 6,200 Tablets) Component
mg/Tablet Batch Formula (g) 4-CNAB Sodium Salt 76-84 496.0
Recombinant Human Insulin 5.32-5.88 35.1 (142.5-157.5 Units)
Povidone USP (Kollidon 90F) 0.38-0.42 2.2 Dibasic Calcium
Phosphate, 35.9-39.7 195.2 Anhydrous, USP Magnesium Stearate, NF
1.14-1.26 6.7 Impalpable Powder Total Weight (mg) 118.8-131.3
735.2
Example 23
Human Clinical Study of Orally Administered Insulin
Six healthy male subjects between the ages of 18 and 40 were orally
administered one tablet or capsule, depending on the treatment
period indicated below after an 8-hour fast the previous night.
Glucose and insulin values were obtained from blood samples fifteen
minutes prior to dosing (t=0) and 5, 10, 15, 20, 25, 30, 35, 40,
45, 50, 60, 90 and 120 minutes after dosing. After receiving the
first tablet or capsule, the subject underwent at least a 72 hour
washout period before receiving the next tablet or capsule.
The administration regimen was as follows:
TABLE-US-00018 TABLE 19 Treatment Period Summary of Dosage
Preparation Details A Wet granulation tablet Example 22 B Rotary
evaporation tablet Example 10 C Rotary evaporation capsule Example
11 D Rotary evaporation tablet Example 12 E Rotary evaporation
capsule Example 13
Results for the treatment regiment are set forth below:
TABLE-US-00019 TABLE 20 Insulin Mean PK Results obtained from
Individual Baseline-adjusted Insulin Concentrations Cmax Tmax
AUClast New/Reference New/Reference Treatment (.mu.U/mL) (min)
(.mu.U/mL * min) Cmax ratio AUC ratio A N 6 6 6 N/A N/A Mean 15.250
19.167 346.250 SD 10.064 2.041 227.404 Min 4.50 15.00 40.00 Max
31.00 20.00 700.00 CV % 66.0 10.6 65.7 B N 6 6 6 1.8 1.2 Mean
27.500 19.167 422.708 SD 9.925 10.685 256.758 Min 14.50 10.00
133.75 Max 41.50 40.00 860.00 CV % 36.1 55.7 60.7 C N 5 5 5 Mean
8.800 35.000 260.000 SD 7.497 33.727 313.358 Min 0.50 10.00 11.25
Max 21.00 90.00 805.00 CV % 85.2 96.4 120.5 C N 5 5 5 0.2 0.4
(without Mean 5.200 41.000 128.000 outlier- SD 3.347 46.287 73.912
Subject 4, Min 0.50 10.00 11.25 90 min Max 8.50 120.00 200.00
timepoint) CV % 64.4 112.9 57.7 D N 6 6 6 0.3 0.3 Mean 9.333 10.000
110.000 SD 4.215 3.162 59.713 Min 1.00 5.00 7.50 Max 12.50 15.00
172.50 CV % 45.2 31.6 54.3 E N 5 4 5 0.4 0.4 Mean 5.600 38.750
140.500 SD 6.004 37.053 123.392 Min 0.00 5.00 0.00 Max 15.50 90.00
273.75 CV % 107.2 95.6 87.8
TABLE-US-00020 TABLE 21 Insulin Mean PK Results obtained from
Individual Insulin Concentrations Cmax Tmax AUClast New/Reference
New/Reference Treatment (.mu.U/mL) (min) (.mu.U/mL * min) Cmax
ratio AUC ratio A N 6 6 6 N/A N/A Mean 30.333 19.167 1882.917 SD
11.343 2.041 435.067 Min 16.00 15.00 1107.50 Max 44.00 20.00
2222.50 CV % 37.4 10.6 23.1 B N 6 6 6 1.6 1.2 Mean 47.167 19.167
2286.250 SD 14.148 10.685 1117.921 Min 21.00 10.00 747.50 Max 59.00
40.00 4222.50 CV % 30.0 55.7 48.9 C (*) N 6 6 6 0.6 0.8 Mean 18.667
27.500 1562.083 SD 4.179 45.689 247.454 Min 12.00 0.00 1127.50 Max
24.00 120.00 1777.50 CV % 22.4 166.1 15.8 D N 6 6 6 0.8 0.9 Mean
24.500 10.000 1640.417 SD 6.863 3.162 522.110 Min 18.00 5.00 867.50
Max 36.00 15.00 2500.00 CV % 28.0 31.6 31.8 E N 6 6 6 0.9 0.9 Mean
26.167 26.667 1744.167 SD 15.052 34.303 414.203 Min 16.00 0.00
1102.50 Max 54.00 90.00 2222.50 CV % 57.5 128.6 23.7
(*) Insulin concentration Measured at 90 min in Subject 4 was
considered an outlier hence not included in the PK analysis.
Model-independent pharmacokinetic metrics were calculated using
WinNonlin (v 4.5, Scientific Consulting, Inc.) from individual
plasma concentration data. This program analyzes data using the
standard methods described by Gibaldi and Perrier. The area under
the plasma concentration-time curve (AUC) was estimated by the
linear trapezoidal rule.
"Baseline" is defined as average plasma insulin concentrations as
assessed prior to study drug administration (i.e. -15 and 0 minute
samples averaged). Adjusted concentrations were obtained by
subtracting the individual baseline from each individual time point
(Ct--Co). Negative values were not included in the data
analysis.
Results for the adjusted-mean insulin profiles are shown in FIGS.
13 (without outlier) and 14 (with outlier).
Example 24
Human Clinical Study of Orally Administered Insulin
The protocol used in Example 23 was used for the following
treatment regimens:
TABLE-US-00021 TABLE 22 Treatment Period Summary of Dosage
Preparation Details A Rotary Evaporation Tablets Example 10 B
Rotary Evaporation Tablets Example 14 C Rotary Evaporation Tablets
Example 15 D Rotary Evaporation Tablets Example 16 E Rotary
Evaporation Tablets Example 17 F Rotary Evaporation Tablets Example
18
Results for the treatment regiment are set forth below:
TABLE-US-00022 TABLE 23 Insulin Mean PK Results obtained from
Individual Baseline-adjusted Insulin Concentrations Cmax Tmax
AUClast Treatment (.mu.U/mL) (min) (.mu.U/mL * min) A N 6 6 6 Mean
30.633 17.500 795.615 SD 20.977 5.244 542.094 Min 10.86 10.00
331.76 Max 66.62 25.00 1742.30 CV % 68.5 30.0 68.1 B N 6 6 6 Mean
22.441 13.333 312.535 SD 16.489 2.582 214.398 Min 8.00 10.00 118.83
Max 52.00 15.00 649.80 CV % 73.5 19.4 68.6 C N 6 6 6 Mean 28.546
21.667 741.708 SD 23.848 14.024 737.074 Min 6.05 5.00 100.93 Max
69.20 45.00 1787.75 CV % 83.5 64.7 99.4 D N 6 6 6 Mean 29.421
16.667 575.435 SD 17.155 4.082 384.295 Min 13.56 10.00 176.14 Max
53.08 20.00 1210.13 CV % 58.3 24.5 66.8 E N 6 6 6 Mean 18.556
15.833 303.702 SD 14.849 2.041 304.338 Min 1.49 15.00 13.35 Max
39.25 20.00 799.38 CV % 80.0 12.9 100.2 F N 6 6 6 Mean 20.971
19.167 536.952 SD 16.710 9.704 528.919 Min 2.14 5.00 15.06 Max
44.11 30.00 1312.61 CV % 79.7 50.6 98.5
TABLE-US-00023 TABLE 24 Insulin Mean PK Results obtained from
Individual Insulin Concentrations Cmax Tmax AUClast Treatment
(.mu.U/mL) (min) (.mu.U/mL * min) A N 6 6 6 Mean 41.945 17.500
1905.513 SD 23.681 5.244 880.650 Min 14.94 10.00 794.20 Max 81.36
25.00 3251.53 CV % 56.5 30.0 46.2 B N 6 6 6 Mean 35.740 13.333
1590.567 SD 14.956 2.582 246.447 Min 20.30 10.00 1199.00 Max 63.19
15.00 1961.45 CV % 41.8 19.4 15.5 C N 6 6 6 Mean 40.807 21.667
1955.696 SD 24.954 14.024 896.595 Min 15.60 5.00 1032.25 Max 84.17
45.00 3295.53 CV % 61.2 64.7 45.8 D N 6 6 6 Mean 42.480 16.667
1919.300 SD 18.411 4.082 493.982 Min 26.08 10.00 1363.75 Max 68.64
20.00 2586.25 CV % 43.3 24.5 25.7 E N 6 6 6 Mean 31.770 15.833
1563.100 SD 13.306 2.041 334.769 Min 13.95 15.00 1030.88 Max 49.90
20.00 1984.25 CV % 41.9 12.9 21.4 F N 6 6 6 Mean 33.737 19.167
1861.629 SD 16.049 9.704 654.066 Min 17.02 5.00 1271.05 Max 53.39
30.00 2969.95 CV % 47.6 50.6 35.1
Results based on the adjusted mean insulin profiles are set forth
in FIG. 15
Example 25
Human Clinical Study of Orally Administered Insulin
The protocol used in Example 23 was used for the following
treatment regimens:
TABLE-US-00024 TABLE 25 Treatment Period Summary of Dosage
Preparation Details A Gelatin-Based Tablet Example 21 B
Co-lyophilized Tablets Example 8 C Rotary Evaporation Tablets
Example 19 D Rotary Evaporation Tablets Example 20 E Wet
granulation Tablets Example 22 F Co-lyophilized Tablets Example
9
Results for the treatment regiment are set forth below:
TABLE-US-00025 TABLE 26 Insulin Mean PK Results obtained from
Individual Baseline-adjusted Insulin Concentrations Cmax Tmax
AUClast New/Reference New/Reference Treatment (.mu.U/mL) (min)
(.mu.U/mL * min) Cmax ratio AUC ratio A N 6 6 6 2.6 3.6 Mean 30.633
17.500 764.871 SD 20.977 5.244 508.089 Min 10.86 10.00 331.76 Max
66.62 25.00 1629.01 CV % 68.5 30.0 66.4 B N 6 6 6 0.9 1.3 Mean
10.531 32.500 286.569 SD 12.685 43.215 284.348 Min 1.33 10.00 12.68
Max 33.61 120.00 731.20 CV % 120.5 133.0 99.2 C N 6 6 6 1.0 1.2
Mean 12.203 15.000 254.679 SD 11.976 3.162 256.555 Min 4.89 10.00
50.65 Max 36.15 20.00 755.21 CV % 98.1 21.1 100.7 D N 6 6 6 1.6 1.9
Mean 19.013 13.333 415.721 SD 24.735 6.055 601.162 Min 2.12 5.00
9.80 Max 67.82 20.00 1576.64 CV % 130.1 45.4 144.6 E N 6 6 6 N/A
N/A Mean 11.693 17.500 213.752 SD 10.033 8.216 180.716 Min 0.69
10.00 1.73 Max 26.70 30.00 415.56 CV % 85.8 46.9 84.5 F N 6 6 6 0.8
0.7 Mean 9.092 15.000 142.221 SD 5.539 8.367 77.332 Min 1.83 10.00
4.56 Max 18.54 30.00 232.71 CV % 60.9 55.8 54.4
TABLE-US-00026 TABLE 27 Insulin Mean PK Results obtained from
Individual Insulin Concentrations Cmax Tmax AUClast New/Reference
New/Reference Treatment (.mu.U/mL) (min) (.mu.U/mL * min) Cmax
ratio AUC ratio A N 6 6 6 1.4 1.6 Mean 32.098 36.667 1966.079 SD
13.956 40.947 963.466 Min 9.85 15.00 800.78 Max 47.49 120.00
3345.18 CV % 43.5 111.7 49.0 B N 6 6 6 1.0 1.1 Mean 21.730 32.500
1379.888 SD 10.133 43.215 281.651 Min 14.06 10.00 1151.90 Max 38.54
120.00 1922.78 CV % 46.6 133.0 20.4 C N 6 6 6 1.1 1.2 Mean 23.873
15.000 1437.488 SD 12.681 3.162 401.442 Min 12.92 10.00 927.30 Max
48.83 20.00 2129.28 CV % 53.1 21.1 27.9 D N 6 6 6 1.3 1.2 Mean
29.630 13.333 1492.971 SD 25.993 6.055 895.031 Min 7.20 5.00 398.93
Max 78.99 20.00 2857.18 CV % 87.7 45.4 59.9 E N 6 6 6 N/A N/A Mean
22.507 17.500 1239.967 SD 8.105 8.216 244.282 Min 14.67 10.00
878.80 Max 32.70 30.00 1507.50 CV % 36.0 46.9 19.7 F N 6 6 6 0.8
0.8 Mean 18.093 15.000 1030.767 SD 6.660 8.367 287.163 Min 11.84
10.00 648.45 Max 29.57 30.00 1360.88 CV % 36.8 55.8 27.9
Results based on the adjusted mean insulin profiles are set forth
in FIG. 16
Example 26
Human Clinical Study of Orally Administered Insulin
145 humans patients having type 2 diabetes who were failing
metformin monotherapy were enrolled in a 90 day randomized
double-blind placebo-controlled study. The patients remained on
their metformin regimen, which varied from 125 mg-3000 mg per day
individualized for each patient. 141 patients completed the
study.
The patients were separated into 4 treatment groups as follows:
TABLE-US-00027 Group Insulin Dose Dosing Regimen 1 (n = 35) Tablet
of Example 22 2 insulin tablets, 4 times daily (150 IU of insulin
each) 2 (n = 35) Tablet of Example 22 2 insulin tablets, 2 times
daily (150 IU of insulin) 2 placebo tablets, 2 times daily 3 (n =
36) Tablet of Example 22 1 insulin tablet + 1 placebo (150 IU of
insulin) tablet, 4 times daily 4 (n = 35) Placebo 2 placebo
tablets, 4 times daily
Hemoglobin Alc counts were obtained about three weeks prior to
beginning the study (screening) and just prior to the first
administration of the oral insulin (t=0) or (baseline).
Changes in HbA1c levels at the conclusion of the 90 day study for
the four groups (relative to baseline) are shown in FIG. 17.
FIGS. 18 and 19 shows the difference between Hemoglobin Alc level
at screening and at baseline for each of the subjects.
FIG. 20 is a bar graph of the changes in HbA1c level at 90 days
compared to baseline for populations in groups 1 and 4 having a
difference in HbA1c levels between screening and baseline of, for
Group 1, 0-1.1, 0-0.5 and 0-0.3 and, for Group 4, 0-1, 0-0.5 and
0-0.3.
FIG. 21 is a bar graph of the change in HbA1c values after 90 days
(compared to baseline) for patients in groups 1 and 4 having
particular baseline HbA1c values and a difference in the HbA1c
values from screening to baseline of 0-0.3. The first bar
represents absolute changes in HbA1c levels (t=0 vs. t=90) for
those subjects in Group I having baseline HbA1c levels ranging from
7 to 8.9 and a 0-0.3 variation of HbA1c levels between screening
and at baseline. The second bar represents absolute changes in
HbA1c levels for a subpopulation of Group 1 having baseline HbA1c
levels of 7.5 to 8.9 and a 0-0.3 variation of HbA1c levels between
screening and at baseline. The third bar represents a still
narrower subpopulation--those patients of Group I having baseline
HbA1c levels of 8 to 8.9 and a 0-0.3 variation of HbA1c levels
between screening and at baseline.
FIGS. 22-23 compare the changes in HbA1c levels for Groups 1 and 4
for those patients having a 0-0.3 variation of HbA1c levels between
screening and at t=0, with baseline HbA1c levels between 8 and 8.9.
For this population, FIG. 22 depicts changes in HbA1c levels across
the 90 days for groups 1 and 4 and FIG. 23 depicts the number of
patients reaching specified HbA1c target levels at the end of the
study. FIG. 24 sets forth changes from baseline for C-Peptide, FBG,
Fructosamine, HbA1c, Insulin and Proinsulin.
Amongst the participants in the study there were no significant
adverse events, no episodes of severe hypoglycemia, or weight gain
amongst groups I-III. Incidents of mild to moderate hypoglycemia
and antibodies in groups 1-3 were comparable to those found in
group 4 (placebo).
* * * * *